Boyd M R, Stiko A, Statham C N, Jones R B
Biochem Pharmacol. 1982 Apr 15;31(8):1579-83. doi: 10.1016/0006-2952(82)90383-5.
Because endogenous glutathione is known to participate in the detoxification of highly reactive, hepatotoxic drug metabolites, we studied the role of this substance in the pulmonary toxicity of 4-ipomeanol [1-(3-furyl)-4-hydroxypentanone] in rats. 4-Ipomeanol was an appropriate model for these studies since previous investigations have indicated that an alkylating metabolite, formed in situ, is responsible for selective lung damage by 4-ipomeanol. Toxic doses of 4-ipomeanol preferentially depleted rat lung glutathione. Pretreatment of animals with piperonyl butoxide, an inhibitor of the metabolic activation of 4-ipomeanol, prevented both the depletion of lung glutathione and the pulmonary toxicity of 4-ipomeanol. Prior depletion of lung glutathione by diethylmaleate increased both the pulmonary covalent binding and the toxicity of 4-ipomeanol, whereas administration of cysteine and cysteamine decreased both the covalent binding and the toxicity. These in vivo studies, in conjunction with previous in vitro studies which showed inhibitory effects of sulfhydryl compounds on the covalent binding of 4-ipomeanol, are consistent with the view that pulmonary glutathione plays a protective role against pulmonary alkylation and lung toxicity by 4-ipomeanol, probably by reacting with the toxic metabolite(s) to form nontoxic conjugate(s). Pulmonary glutathione may similarly provide protection against other electrophilic drugs or metabolites that can damage the lungs.
由于已知内源性谷胱甘肽参与高反应性肝毒性药物代谢产物的解毒过程，我们研究了该物质在大鼠中对4-异亚丙基丙酮[1-(3-呋喃基)-4-羟基戊酮]肺毒性的作用。4-异亚丙基丙酮是这些研究的合适模型，因为先前的研究表明，原位形成的一种烷基化代谢产物是4-异亚丙基丙酮导致选择性肺损伤的原因。4-异亚丙基丙酮的毒性剂量优先消耗大鼠肺中的谷胱甘肽。用胡椒基丁醚（一种4-异亚丙基丙酮代谢活化抑制剂）预处理动物，可防止肺谷胱甘肽的消耗以及4-异亚丙基丙酮的肺毒性。用马来酸二乙酯预先消耗肺谷胱甘肽会增加4-异亚丙基丙酮的肺共价结合和毒性，而给予半胱氨酸和半胱胺则会降低共价结合和毒性。这些体内研究，结合先前的体外研究（显示巯基化合物对4-异亚丙基丙酮共价结合有抑制作用），与以下观点一致：肺谷胱甘肽可能通过与有毒代谢产物反应形成无毒共轭物，对4-异亚丙基丙酮引起的肺烷基化和肺毒性起到保护作用。肺谷胱甘肽可能同样为抵御其他可损害肺部的亲电药物或代谢产物提供保护。
